Lyme disease is caused by Borrelia burgdorferi and is transmitted primarily by tick species Ixodes scapularis. Ticks can attach to any part of the human body but are often found in hard-to-see areas such as the groin, armpits, and scalp. In most cases, the tick must be attached for 36 to 48 hours or more before the spirochetes can be transmitted. Very few people affected with Lyme disease recall a tick bite. B. burgdorferi have two morphological forms, a spiral form and a spheroplast form. Survival strategies of B. burgdorferi include: antigenic variation, physical sequestration, intracellular invasion, and immune system supression.

Hard-bodied ticks of the genus Ixodes are the primary vectors of Lyme disease. The majority of Ixodes–vectored human disease is caused by I. scapularis, I. pacificus, I. ricinus, and I. persulcatus, so they are also known as ‘bridge’ vectors.[1] Infection from adult ticks is higher than nymph stage ticks in terms of pathogens infectious to humans, but the majority of infections are caused by ticks in the nymph stage during late spring and summer.[2][3] In most cases, the tick must be attached for 36 to 48 hours or more before the spirochetes can be transmitted.[4] It takes at least 36 hours for spirochetes to multiply and migrate to the salivary glands from the midgut.[5] In Europe, the commonly known tick called sheep tick, castor bean tick, or European castor bean tick (Ixodes ricinus) is the primary vector.[1] In North America, the black-legged tick, or deer tick, (Ixodes scapularis) has been identified as the primary vector of the disease’s spread on the east coast.[1][6] In the Pacific region of North America, the Western black legged tick (Ixodes pacificus) is the primary vector.[1][6] The taiga tick (Ixodes persulactus) is a predominant species of tick in Europe, Central and Northern Asia, China, and Japan.[7] Only 20% of individuals infected with Lyme disease by the deer tick are aware of having had any tick bite, making early detection difficult in the absence of a rash.[8]
Ixodes pacificus – Source: PHIL #8686 Ixodes ricinus – Source: Wikimedia commons Ixodes persulactus – Source: Wikimedia commons

• The lone star tick (Amblyomma americanum), which is found throughout the Southeastern U.S. as far West as Texas and increasingly in Northeastern states, is another potential vector.^[9]
• These tick bites usually go unnoticed due to the small size of the tick in its nymphal stage, as well as tick secretions that prevent the host from feeling any itch or pain from the bite.
• It was once thought to be a vector, although recent studies demonstrate that this tick species is not a competent vector of Borrelia burgdorferi sensu lato.^[10]
• The lone star tick (Amblyomma americanum) is associated with southern tick-associated rash illness (STARI or Masters’ disease), Tularemia, and Ehrlichiosis.^[11]

• While Lyme spirochetes have been found in insects other than ticks, reports of actual infectious transmission appear to be rare.^[12][13]
• Sexual transmission has been reported. Lyme spirochetes have been found in semen and breast milk; however, transmission of the spirochetes by these routes is not known to occur.^[14][15][16]
• Congenital transmission of Lyme disease can occur from an infected mother to fetus through the placenta during pregnancy. However, prompt antibiotic treatment appears to prevent fetal harm.^[17]

• The primary reservoir host of B. burgdorferi is rodents. These rodents are infested by I. scapularis.
• The white-footed mouse (Peromyscus leucopus) is the most common rodent infected by B. burgdorferi.^[18]
• Other reservoirs may include voles, chipmunks, squirrels, raccoons, skunks, birds, and reptiles such as lizards.
• It is predicted that the density of infected nymphal stage of ticks may be lower in areas where predators of primary reservoir hosts, particularly red foxes (Vulpes vulpes), are more active. The reason for this may include:^[19]
  • Direct effect: Predation of reservoir hosts.
  • Indirect effect: Decreased movement and increased refuge due to presence of active predator.

• Ixodes scapularis is also a vector for Anaplasma phagocytophilum (previously referred to as Ehrlichia phagocytophila) and Babesia microti.^[20]
• Anaplasma phagocytophilum causes human granulocytic anaplasmosis (HGA), previously known as human granulocytic ehrlichiosis.
• Babesia microti causes babesiosis.
• Sometimes, patients may be coinfected with two or more pathogens.
• Presence of flu-like symptoms (fever, chills, and headache) in patients of Lyme disease without erythema migrans may indicate concurrent infection with human granulocytic anaplasmosis (HGA) and/or babesiosis.^[21]
• Coinfection should be considered in the case of prolonged flu-like symptoms that fail to respond to Lyme disease treatment.
• CBC should be considered as initial investigation for patient thought to have coinfection.

• B. burgdorferi enters the bloodstream through saliva during a tick bite.^[22]
• After the incubation period (around 3-30 days), B. burgdorferi migrates outwards in skin, manifesting as erythema chronicum migrans. It is then disseminated to other organs including multiple skin sites manifesting as multiple erythema migrans.^[23]
• B. burgdorferi is a very slow growing organism. Its doubling time is 12-24 hours (in contrast with bacterial pathogens such as Streptococcus and Staphylococcus, which have a doubling time of 20-30 minutes).
• B. burgdorferi has an axial filament composed of flagella that runs lengthwise between its cell wall and outer membrane like other spirochetes. This structure allows B. burgdorferi to move efficiently through viscous media (such as connective tissue) in a corkscrew fashion.
• This helps B. burgdorferi disseminate throughout the body in the days to weeks after infection.
• B. burgdorferi penetrates deep into the tissue where the immune system and antibiotics are unable to reach.
• B. burgdorferi has two morphological forms, a spiral form and a spheroplast form (cysts, granules). The existence of B. burgdorferi spheroplasts, which lack a cell wall, has been documented in the following models:
  • In vitro model^{[24][25][26][27]}
  • In vivo model^[28][25][29]
  • Ex vivo model^[30]
• The spiral form requires energy to convert to the spheroplast form. This shows that the spheroplast form has a survival function, and it is not merely an end stage degeneration product.^[24]
• The spheroplasts are virulent and infectious and survive under adverse environmental conditions. Once the conditions are more favorable, they revert back to the spiral form in vitro.^[31][32]
• B. burgdorferi spheroplasts play a key factor in the relapsing, persistant nature of Lyme disease due to:
  • Spheroplasts have dramatically reduced surface area for immune surveillance as compared to spiral form.
  • Spheroplasts express different surface proteins; current tests detect antibodies to surface proteins of the spiral form, which may result in seronegative disease (i.e. false-negative antibody tests).
  • B. burgdorferi spheroplasts are generally not susceptible to the antibiotics traditionally used for Lyme disease. They have shown sensitivity in vitro to antiparasitic drugs to which the spiral form of B. burgdorferi is not sensitive. These drugs include:
    • Metronidazole^[33]
    • Tinidazole^[34]
    • Hydroxychloroquine^[35]

• B. burgdorferi is susceptible to a number of antibiotics in vitro, but the efficacy of antibiotics in vivo has contradictory reports. Especially when treatment is delayed and disease is disseminated, B. burgdorferi has the ability to persist in humans and animals for months to years even after a strong immune response and antibiotic treatment. Numerous studies have demonstrated persistence of infection despite antibiotic therapy.^[36][37][38]
• Survival strategies of B. burgdorferi include: ^[39]
  • Antigenic variation
    • B. burgdorferi has the ability to vary its surface proteins in response to attack by the immune system.^[40]
    • This is due to the complex genome of B. burgdorferi which helps in evading the immune system and establishing a persistant infection.^[41]
  • Physical sequestration
    • B. burgdorferi is sequestered in sites such as central nervous system that are inaccessible to the immune system and antibiotics.^[42]
    • Evidence suggests that B. burgdorferi penetrates the blood-brain barrier by using the fibrinolytic system of the host.^[43]
  • Intracellular invasion
    • B. burgdorferi invades a variety of cells, including:
      • Endothelium^[44]
      • Lymphocytes^[45]
      • Macrophages^[46]
      • Keratinocytes^[47]
      • Synovium^[48][28]
      • Neuronal and glial cells^[49]
    • B. burgdorferi hides inside these cells and evades the immune system. It is also protected against antibiotics to varying degrees, allowing the infection to persist.^[50][51]
  • Immune system suppression
    • The mechanism of immune system suppression observed in B. burgdorferi includes:^[39]
      • Complement inhibition^[52]
      • Induction of anti-inflammatory cytokines such as IL-10
      • Formation of immune complexes
    • Formation of immune complexes in B. burgdorferi might explain the seronegative disease (i.e. false-negative antibody tests of blood and cerebrospinal fluid). Studies have shown that substantial numbers of seronegative Lyme patients have antibodies bound up in these complexes.^[53]

Evidence of a distinct pro-inflammatory immune process has been observed in both acute and antibiotic refractory Lyme disease.

• This pro-inflammatory process is a cell-mediated immunity and results in Th1 upregulation.
• A significant decrease in output of Interleukin-10 (IL-10), an upregulation of Interleukin-6 (IL-6), Interleukin-12 (IL-12), and Interferon-gamma, and dysregulation in TNF-alpha have been observed.^[54]
• Host immune response to infection results in increased levels of Interferon-gamma in serum and lesions of Lyme disease patients that correlate with a greater severity of disease.
• Interferon-gamma alters gene expression in endothelia exposed to B. burgdorferi in a manner that promotes recruitment of T cells and suppresses that of neutrophils.
• IL-10 is generally regarded as an anti-inflammatory cytokine, as it acts on several different cell types to suppress the production of pro-inflammatory mediators.
• Researchers are also beginning to identify microglia as a previously unrecognized source of inflammatory mediator production following infection with B. burgdorferi.
  • Such production may play an important role during the development of cognitive disorders in Lyme neuroborreliosis.
  • This effect is associated with induction of nuclear factor-kappa B (NF-KB) by B. burgdorferi.^[55][56]
• Dysregulation in production of pro-inflammatory cytokines such as IL-6 and TNF-alpha can lead to neuronal damage in patients infected with B. burgdorferi.^[57]
• IL-6 and TNF-Alpha cytokines produce fatigue and malaise, two of the prominent symptoms experienced by patients with post treatment Lyme disease syndrome.^[58]
• IL-6 is also significantly linked to cognitive impairment.^[59]

• A developing hypothesis is that the chronic secretion of stress hormones (specifically glucocorticoids and catecholamines) as a result of Borrelia infection may reduce the effect of neurotransmitters, or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones.^[60][61]
• This process is mediated via the hypothalamic-pituitary-adrenal axis.
• Additionally, tryptophan, a precursor to serotonin, appears to be reduced within the CNS in a number of patients with Lyme disease.^[62]

• It has been found that post treatment Lyme disease syndrome patients have higher amounts of Borrelia-specific forkhead box P3 (FoxP3) than healthy controls, indicating that regulatory T cells, by immunosuppression, might play a role in the development of post treatment Lyme disease syndrome.
• FoxP3 are a specific marker of regulatory T cells.^[63]
• The signaling pathway P38 mitogen-activated protein kinases (p38 MAP kinase) has been identified as promoting expression of pro-inflammatory cytokines from Borrelia.^[64]
• These new and ongoing immunological studies suggest that cell-mediated immune disruption in Lyme patients amplifies the inflammatory process, often rendering it chronic and self-perpetuating. It is regardless of whether the Borrelia bacterium is still present in the host. It might also suggest an autoimmune pattern.^[65]

• Biopsy of erythema migrans shows:
  • Dermal and epidermal involvement in center of lesion
  • Dermal involvement at the periphery

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